FACULTY OF HEALTH SCIENCESDEPARTMEMNT OF medical imaging and radiation

sciences Radiographic practice III therapy (rpT211)

THE USE OFHYPERTHERMIA IN ONCOLOGY

NAME: OUPA STEVEN MOTSHWENENGSTUDENT NUMBER: 2013 722 17

COURSE: NATIONAL DIPLOMA RADIOGRAPHY (THERAPY)MODULE LECTURER: Mrs F. Bhyat (m.tech)SUBMISSION DATE: 21 august 2015

Table of Contents

List of Figures........................................................................................................................- 1 -

1. Introduction.....................................................................................................................- 2 -

2. Application of Hyperthermia..........................................................................................- 3 -

3. Use of Hyperthermia in Oncology..................................................................................- 3 -

3.1. As an Adjuvant Modality........................................................................................- 3 -

3.2. Urinary Bladder Cancer...........................................................................................- 4 -

3.3. Head and Neck Cancers...........................................................................................- 5 -

3.4. Cervical Cancer.......................................................................................................- 6 -

3.5. Melanoma................................................................................................................- 7 -

4. Clinical value and Justification.......................................................................................- 8 -

5. Conclusion....................................................................................................................- 10 -

References............................................................................................................................- 11 -

List of Figures

Figure 1. Synergo SB-TS 101 system during treatment.........................................................- 5 -

Figure 2. Administration of local hyperthermia to the neck..................................................- 5 -

Figure 3. Clinical trial results.................................................................................................- 8 -

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1. Introduction

Cancer has been reported to be the leading death cause globally accounting for 8.2 million

deaths in the year 2012 (Cancer fact sheet, 2015). With an attempt to combat this life

threatening disease, many therapies have been discovered, trialled and established. These

include and not limited to surgery, chemotherapy and radiotherapy (Symonds, Deehan, Mills

& Meredith, 2012:297-298). These treatment modalities have been successful in a number of

ways.

Nonetheless, there are ongoing studies on new modalities and improvements on the current

ones, in an endeavour to reduce cancer related mortality and morbidity and increase patient

survival and quality of life. The most recently studied modalities in oncological management

include and not limited to immunotherapy, targeted therapy and hyperthermia. However,

dissimilar to immunotherapy and targeted therapy, hyperthermia is not mostly used nor is it

mostly studied as a primary treatment uni-modality.

The focus of study on hyperthermia in oncology is its ability to enhance the efficacy of other

modalities such as radiotherapy and/or chemotherapy, thus it is used in conjunction with other

modalities (Huilgol, Gupta & Dixit, 2010: 24). This assignment focuses on the rationale for

the use of hyperthermia in cancer treatment, critical analysing its efficacy on the improvement

in the management of bladder, head and neck, cervical cancers and melanomas. Furthermore,

various methods by which hyperthermia can be applied, its clinical value and the justification

of its use in the current oncological setting will be discussed.

Hyperthermia can be defined as a modest artificial elevation of tissue temperature in the range

of 39 to 45 degrees Celsius, which is above physiological level (Datta, Gómez Ordóñez,

Gaipl, Paulides, Crezee, Gellermann, Marder, Puric & Bodis, 2015:1; Franckena, 2012:543;

Westermann, Mella, Van Der Zee, Jones, Van Der Steen-Banasik, Koper, Uitterhoeve, De

Wit, Van Der Velden, Burger, Schem, Van Der Wilt, Dahl, Prosnitz & Van Tinteren,

2012:550). It is one of the oldest cancer therapies dating back to 5000 BC and it was also

acknowledged by one of the greatest pioneers of medicine, Hippocrates of Kos (Datta et al,

2015:1). Not only is it one of the oldest cancer treatments but it is also an evolving

oncological therapy modality (Franckena, 2012:543), thus as old as it is but it is still one of

the study focuses in the current oncological setting.

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2. Application of Hyperthermia

Hyperthermia has a direct cytotoxic effect, consequently the ability to cause direct tumour cell

death (Lammers, Witjes, Inman, Leibovitch, Laufer, Nativ & Colombo, 2011:82).

Nonetheless, it is most commonly used as a thermal sensitizer adjuvant to either

chemotherapy or radiotherapy (Datta et al, 2015:2; Franckena, 2012:544; Halachmi,

Moskovitz, Maffezzini, Conti, Verweij, Kedar, Sandri, Nativ & Colombo, 2011:260; Jin, Xie,

Hu, Gao, Zhou, Zhang, Du, Wang, Zhao, Zhang, Shen, Liao & Tang, 2013:733). There are

several methods and techniques in which hyperthermia can be applied and these will differ

depending on whether it is used alone, with radiotherapy or with chemotherapy and also on a

diagnosis basis.

The application of hyperthermia in a clinical setting is divided into three divisions, namely;

the whole body, the regional and the local hyperthermia. In addition to this, the heating

techniques are categorized into two, there is superficial heating which refers to heating of less

than 4cm from skin surface and deep heating which refers to heating of greater than 4cm from

skin surface. Terms ‘external’ and ‘internal’ or ‘invasive and intraluminal’ can also be used in

place of ‘superficial’ and ‘deep’. There are two types of hyperthermia induction mechanisms,

the radiative electromagnetic hyperthermia and ultrasound hyperthermia. Both mechanisms

achieve hyperthermia induction by means of thermal conduction by a circulating liquid and

exposure by either type of the waves (Datta et al, 2015:2-3). Some specific hyperthermia

systems will be mentioned in specific diagnoses discussions.

3. Use of Hyperthermia in Oncology

3.1. As an Adjuvant Modality

As alluded above, there are two main effects of hyperthermia on tumour cells. Direct

cytotoxicity, due to hyperthermia’s ability to alter intracellular metabolism, damage DNA,

impair proliferation of cells and increase tumour cell death (Cassidy, Bissett & Spence OBE,

2002:650; Lammers et al, 2011:82), this takes place and temperatures equal to and greater

than 42 degrees Celsius (Franckena, 2012:544). Secondly, it can be used as a thermal

sensitizer to enhance the effect of either chemotherapy or radiotherapy (Datta et al, 2015:2;

Franckena, 2012:544; Halachmi et al, 2011:260; Jin et al, 2013:733). The latter will be

discussed later, in terms of specific diagnoses.

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In radiotherapy, hyperthermia achieves sensitization by increasing the sensitivity of hypoxic

and malnourished cells, preventing the repair of radiation induced DNA damage, sensitizing

the cell cycle S phase cells and by increasing some tumour cells’ sensitivity to hyperthermia.

This is achieved at temperature ranges of 41 to 43 degrees Celsius. Moreover, hyperthermia

possesses the same radiobiological advantages as high energy linear transfer (LET) radiations

such as C particle. Hyperthermia is also compatible and even more advantageous when used

in conjunction with highly effective radiotherapy modalities such as proton therapy and

brachytherapy. Due to its characteristics and mode of mechanism, hyperthermia allows for

radiotherapy dose escalation (Datta et al, 2015:2&9) consequently resulting in higher tumour

control probability.

In chemotherapy, the sensitization of cancer cells to chemotherapeutic drugs entirely depends

on the drug administered. There are drugs of independent action, which hyperthermia cannot

be used to increase their effectiveness, these include drugs like 5-fluorouracil, methotrexate

and taxane. There is another group of drugs that through research, they have been found to

have an increase in tumour cell kill with an increase in temperature. This group includes

doxorubicin, cyclophosphamide and ifosphamide. The last group shows a distinct

sensitization at temperature ranges of 41 to 43 degrees Celsius, these are drugs such as

cisplatin, carboplatin and bleomycin (Datta et al, 2015:2).

3.2. Urinary Bladder Cancer

Cancers of the urinary bladder are divided into two categories, superficial (non-invasive) and

deep (invasive). The way to treat non-invasive bladder cancer is by a conservative approach

by transurethral resection followed by intravesical chemotherapy. Surgery (cystectomy) and

radiotherapy are indicated for invasive cancer (Halachmi et al, 2011:259; Lammers et al,

2011:82; Symonds et al, 2012: 489&491). Even though a conservative method is used for

non-invasive bladder cancer (NIBC), the risk of recurrence and progression is high (Halachmi

et al, 2011:259). Intravesical chemotherapy has being used for recurrence and progression

(Symonds et al, 2012: 491). However, intravesical chemo is associated with unfavourable

toxicities and suboptimal effectiveness (Lammers et al, 2011:82) and can subsequently lead to

cystectomy which comes with the risk of post-operation morbidity, intra-operation mortality

and impaired quality of life (Halachmi et al, 2011:260).

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Figure 1. Synergo SB-TS 101 system during treatment. Lammers et al (2011:82)

Due to the all the risks mentioned above, there have been developments in the management of

NIBC. One of these developments is the adjuvant combination of intravesical chemotherapy

and hyperthermia referred to as chemohyperthermia (Halachmi et al, 2011:260; Lammers et

al, 2011:82) This is administered by local hyperthermia using a system called Synergo

Hyperthermia System (see figure 1). A research review conducted by Lammers et al

(2011:82&88-90) demonstrates that chemohyperthermia reduces the risk of recurrence by

59%, results in an overall bladder preservation of 87.6% and progression is reported to be

between 0 to 8%. Another study reported a bladder preservation rate of 88%. Thus

chemohyperthermia is an effective treatment to prevent NBIC recurrence and it is also safe

and tolerable (Halachmi et al, 2011:261&264).

3.3. Head and Neck Cancers

Figure 2. Administration of local hyperthermia to the neck. (2010). Available from: http://fightoralcancer.org/hyperthermia-combined-with-low-dose-radiation

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The management of head and neck cancers necessitates expert incorporation of multiple

therapies. Radiotherapy with concomitant chemotherapy has been a standard approach to

certain head and neck cancers (larynx, hypopharynx etc.). This bimodality therapy with

cisplatin has resulted in improved survival rate in head and neck cancer patients. However,

the integration of another modality such as hyperthermia can increase the efficacy of the

disease management. Administration of local hyperthermia (see figure 2) as an additive to the

standard chemoradiation has shown to increase the effectiveness of this treatment approach.

This has been proved in a study that showed a remarkable 70% complete response to

treatment following radiation and hyperthermia (Huilgol et al, 2010:21).

It is true that chemoradiation is a standard care in head and neck cancers and it delivers

improved survival rates when compared to a single modality. Nonetheless, this bimodality

therapy has been associated with increased acute mucosal and skin toxicity and chronic

toxicity. Furthermore, a number of neoplasms that are relatively chemoresistant and

radioresistant due to tissue hypoxia have remained incurable even after chemoradiation

(Huilgol et al, 2010:24)

In the light of the abovementioned facts, hyperthermia has the ability to overcome tissue

hypoxia and increase blood perfusion, consequently making cells chemo and radiosensitive

and susceptible to death (Huilgol et al, 2010:24). A study was carried out to validate the

feasibility and efficacy of a trimodality (chemoradiation plus hyperthermia) approach in the

management of head and neck cancers. Patients were offered a radiation total dose of 70Gy in

7 weeks, with weekly chemotherapy using either cisplatin of paclitaxel and weekly

hyperthermia sessions of 41 to 43 degrees Celsius for 30 minutes using an 8.2 MHz

radiofrequency (Huilgol et al, 2010:22). The observation was that there were no unfavourable

toxicities and there was a great increase in cure rate (Huilgol et al, 2010:22&24)

3.4. Cervical Cancer

Cancer of the cervix is one of the most common malignancies and cause of mortality, with a

global mortality rate of 275 000 deaths every year (Westermann et al, 2012:549). Radical

surgery has been and remains the treatment of choice for early cervical cancer, advanced

cervical cancers are treated with cisplatin containing chemoradiation (Franckena, 2012:543;

Westermann et al, 2012:549). The employment of chemoradiation over radiotherapy alone in

the management of cervical cancer dates back to over a century ago (Franckena, 2012:549).

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The efficacy of this bimodality therapy is study-proven (Franckena, 2012:543&549;

Westermann et al, 2012:550)

Endless studies are being conducted in oncology in order to improve cancer management and

combat cancer related mortality. Through intensive study and research (Westermann et al,

2012:550) hyperthermia has been found to have an enhancement effect on the therapeutic

mechanism of chemotherapy without additional toxicity, particularly that of cisplatin. Based

on this fact, a trimodality of concurrent chemotherapy and concurrent hyperthermia with

radiotherapy was established in the management of cervical cancer. This was done in order to

improve the efficacy of radiotherapy (Westermann et al, 2012:550).

The tumour microenvironment and physiology prominently influences the response of

tumours to treatment, particularly the flow of blood (Griffin, Dings, Jamshidi-Parsian & Song,

2010:256). In the light of the abovementioned fact, one of the challenges in the management

of cervical cancer with radiotherapy alone it is that bulky tumours comprise of many hypoxic

tumour cells which are also in an acidic and nutrient deprived microenvironment (Franckena,

2012:544).

By increasing tissue temperature levels to 39 degrees Celsius and above, hyperthermia

increases the blood flow thus decreasing hypoxia and nutrient deprivation in tumour cells.

This makes these cells to be more sensitive to both chemotherapy and radiotherapy.

Moreover, increase in blood flow allows for a better delivery of chemotherapy drugs to the

area of interest (Franckena, 2012:544). Researchers have shown that there is an increase in the

overall survival rate of cervical cancer patients with the addition of hyperthermia to the

standard chemoradiation. Moreover, this improvement was found to be with no addition of

neither treatment related toxicities nor long-term toxicities (Franckena, 2012:544&546).

3.5. Melanoma

Malignant melanoma is one of the most aggressive cancers and it possesses the ability to

rapidly metastasize, which is a worrying feature of this cancer (Jin et al, 2013:725). In

addition to this, the incidence of melanoma is increasing across the globe (Jin et al, 2013:725;

Symonds et al, 2012: 331). Early stage melanomas can be eradicated by surgical resection

(Jin et al, 2013:730; Symonds et al, 2012:334) but this is not the case with late stages of this

cancer, which are characterized by metastatic spread. Late stage melanoma is difficult to

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manage due to the fact that melanoma is resistant to both chemotherapy and radiotherapy thus

it does not respond to either of these therapies (Jin et al, 2013:730).

One of the studied possible therapies that could be integrated into the management of

melanoma is hyperthermia. With clinical experiments reporting hyperthermia to be both

tolerable and clinically practical (Jin et al, 2013:725), Jin et al (2013:727) studied the efficacy

of this therapy in the treatment of malignant melanoma using pathogen free mice as tumour

models. After the establishment of tumour models by transplantation of malignant melanoma

cells into the mice, hyperthermia was administered with temperatures ranging from 45 to 50

degrees Celsius (Jin et al, 2013:727).

The results and findings were that at the exposure of temperatures 43, 45 and 47 degrees

Celsius for 30 minutes, migratory and invasive abilities of the cancerous cells were

suppressed (Jin et al, 2013:730). Based on this finding and others it was concluded that

hyperthermia inhibits the proliferation, invasive and metastatic potential of melanoma cells

and also inhibits the mobility of these cells (Jin et al, 2013:728). Thus it is prospected that

hyperthermia can be an effective adjuvant therapy not for direct cytotoxicity of malignant

melanoma but for supressing the invasiveness and mobility of the remnant cancerous cells

(Jin et al, 2013:733).

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4. Clinical value and Justification

Figure 3. Clinical trial results. Available from www.pyrexar.com

The above discussions suggest that hyperthermia is of a great clinical value, particularly in

oncological management. This suggestion is supported by multiple factors which a few of

them are hereafter explored. Firstly, hyperthermia makes use of heat as a therapeutic agent

which when applied, increases the permeability of the cell membrane and increases blood

perfusion (Lammers et al, 2011:82). This effect is of great clinical advantage in oncology as it

enhances the effect of both radiotherapy and chemotherapy. The above graph (figure 2)

clearly demonstrates the advantage on response rates of using chemotherapy and/or

radiotherapy with hyperthermia against the use of either chemotherapy or radiotherapy alone

in various cancers.

In addition to this, the clinical value of hyperthermia is clearly demonstrated by its impact of

doubling the local control rate and improving patient survival. Its application is of limited

restrictions and low cost (Franckena, 2012:546; Hansen & Roach, 2010: 22). Furthermore, all

these therapeutic benefits come with no addition of toxicity (Franckena, 2012:546; Huilgol et

al, 2010:22) and because it does not add to radiation-induced toxicities, advances in

radiotherapy cannot nullify its beneficial effect (Franckena, 2012:546).

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Oncology is an evolving field thus if hyperthermia is to be employed in this constantly

improving field, mainly the current setting, it has to be with convincing justification.

Previously there was a reduction in the enthusiasm of incorporating hyperthermia into clinical

practice, this was resulted by lack of proper heating and temperature monitoring devices. But

since the commencement of this century there have been improvements in this regard, better

hardware and software that allow for a more safer and effective hyperthermia treatment

delivery have been invented (Datta et al, 2015:2). These advances include the use of

Computed Tomography and Magnetic Resonance derived anatomical models, the non-

invasive online thermometry and simulation guided adaptive hyperthermia. (Datta et al,

2015:6)

One of the disadvantages of hyperthermia previously is that its clinical application was

experience-based thus treatment results varied with expertise and experience of the staff.

(Franckena, 2012:543-544). However, this has now been improved by the introduction of

these new and advanced planning and simulation systems which are more user-friendly (Datta

et al, 2015:8).

5. Conclusion

Based on the findings presented on this critical analysis on the use of hyperthermia in

oncology, the conclusion thereof is as follows. Hyperthermia has a very important role in the

management of various oncological conditions such as melanoma, bladder, head and neck and

cervical cancers. Its role is characterized by enhancing the efficacy of both radiotherapy and

chemotherapy without adding to treatment induced toxicities. The use of hyperthermia is

advocated for in the current oncological setting by multiple authors and researchers and its

clinical value is of great advantage. Even though it has a potential of direct cell killing,

hyperthermia is greatly embraced by the literature as an effective, safe and tolerable adjuvant

therapy.

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The employment of hyperthermia into the current oncological setting would be of much aid in

combating cancer related morbidity and mortality. It is a fact that hyperthermia is a very old

therapy but due to the inadequacies of the methods and equipment used previously there was a

subtle decrease in the enthusiasm of its clinical use. However, current researchers embarked

on the study of this therapy despite the previous findings and conclusions. Due to these

current studies there is resurrection of hope and enthusiasm in hyperthermia, previous

inadequacies are apprehended and thus improvement is achieved. From this I have learned

that it is of great benefit to re-study areas and methods that have previously failed using

different approaches and techniques as this could yield breakthroughs. On the basis of the

research done as part of this assignment there seem to be limited information on the use of

hyperthermia in the treatment of melanoma thus I recommend that more studies should be

done in this respect.

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References

Cancer fact sheet N 297 (2015). Available from:

http://www.who.int/mediacentre/factsheets/fs297/en/

Cassidy, J., Bissett, D. and Spence OBE, R.A. (2002). Oxford Handbook of Oncology.

New York. Oxford University Press Inc.

Datta, N.R., Gómez Ordóñez, S., Gaipl, U.S., Paulides, M.M., Crezee, H.,

Gellermann, J., Marder, D., Puric, E. and Bodis, S. (2015). Local hyperthermia

combined with radiotherapy and-/or chemotherapy: Recent advances and promises for

the future. Elsevier. Available from: http://www.elsevierhealth.com/ journals/ctrv

Franckena, M. (2012). Review of radiotherapy and hyperthermia in primary cervical

cancer. International Journal of Hyperthermia, 28(6):543-548

Griffin, R.J., Dings, R.P., Jamshidi-Parsian, A. and Song, C.W. (2010). Mild

temperature hyperthermia and radiation therapy: Role of tumour vascular

thermotolerance and relevant physiological factors. International Journal of

Hyperthermia, 26(3):256–263

Halachmi, S., Moskovitz, B., Maffezzini, M., Conti, G., Verweij, F., Kedar, D.,

Sandri, S.D., Nativ, O. and Colombo, R. (2011). Intravesical mitomycin C combined

with hyperthermia for patients with T1G3 transitional cell carcinoma of the bladder.

Urologic Oncology: Seminars and Original Investigations, 21:259-264

Hansen, E.K. and Roach M. (2010). Handbook of Evidence-Based Radiation

Oncology. 2nd Edition. New York. Springer

Huilgol, N.G., Gupta, D., and Dixit, R. (2010). Chemoradiation with hyperthermia in

the treatment of head and neck cancer. International Journal of Hyperthermia,

26(1):21-25

Jin, H., Xie, X., Hu, B., Gao, F., Zhou, J., Zhang, Y., Du, L., Wang, X., Zhao, L.,

Zhang, X., Shen, L., Liao Y. and Tang, J. (2013). Hyperthermia inhibits the

proliferation and invasive ability of mouse malignant melanoma through TGF-β1.

Oncology Reports, 29:725-734

Lammers, R.J., Witjes, J.A., Inman, B.A., Leibovitch, I., Laufer, M., Nativ, O. and

Colombo, R. (2011). The Role of a Combined Regimen With Intravesical

Chemotherapy and Hyperthermia in the Management of Non-muscle-invasive Bladder

Cancer: A Systematic Review. European Urology, 60:81-93

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Symonds, P., Deehan, C., Mills, J. A. and Meredith, C. (2012). Walter & Miller’s

textbook of Radiotherapy. 7th Edition. China. Elsevier

Westermann, A., Mella, O., Van Der Zee, J., Jones, E.L., Van Der Steen-Banasik, E.,

Koper, P., Uitterhoeve, A.L., De Wit, R., Van Der Velden, J., Burger C., Schem, B.,

Van Der Wilt, C.L., Dahl, O., Prosnitz, L.R. and Van Tinteren, H. (2012). Long-term

survival data of triple modality treatment of stage IIB–III–IVA cervical cancer with

the combination of radiotherapy, chemotherapy and hyperthermia – an update.

International Journal of Hyperthermia, 28(6):549–553

www.fightoralcancer.org

www.pyrexar.com

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